3-(4&#39;-substituted)-benzyl-ether derivatives of pregnenolone

ABSTRACT

The invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein R1 is C1-8 alkyl, C1-8 alkoxy, CN, NO 2 , amino, COOH, COOCH 3 , OH, N 3 , or halogen and R2 is H, OH, C1-8 alkyl, C1-8 alkoxy, C2-C6 alkenyl, halogen, Bn-O—, Bn- optionally substituted, or Ph- optionally substituted.

FIELD OF THE INVENTION

The present invention relates to synthetic neuroactive steroids and moreparticularly to synthetic Pregnenolone derivatives and their use in amethod for treatment of the human or animal body.

BACKGROUND OF THE INVENTION

Various steroids synthesized in the adrenal glands and gonads arecapable of modulating neuron excitability in the CNS. For thesecompounds the term “neuroactive steroids” has been coined (Majewska etal., 1986), or “neurosteroids” for those that the brain can synthesizede novo (Baulieu, 1991).

Steroid hormones have long been recognized to have sedative, anestheticand anti-seizure properties in animals and humans (Aird, 1944; Aird andGordan, 1951; Gyermek et al., 1967; Green et al., 1978). Studies duringthe past two decades have uncovered that progesterone anddeoxycorticosterone serve as precursors for the endogenous neurosteroids allopregnanolone (5α-pregnane-3α-ol-20-one) and THDOC(5α-pregnane-3α,21-diol-20-one), respectively (Reddy, 2003; 2009a).Testosterone-derived androgens such as androstanediol(5α-androstane-3α,17β-diol) and estradiol can be considered asneurosteroids (Reddy, 2008). Generally, the acute effects ofneurosteroids are not related to interactions with classical steroidhormone receptors that regulate gene transcription. Moreover,neurosteroids are not themselves active at intracellular steroidreceptors. They modulate brain excitability primarily by interactionwith neuronal membrane receptors and ion channels, principally GABA-Areceptors (Lambert et al., 2003; Reddy, 2003; Akk et al., 2009).

In addition to endogenous steroids such as pregnenolone sulfate, DHEA-S,estradiol, or progesterone for which neuroactive properties have beendescribed (Paul and Purdy, 1992; Rupprecht, 1997), synthetic steroidshave been developed recently that share their endogenous counterparts'characteristic of modulating a variety of G-protein-coupled receptorsand ligand-gated ion channels (Gasior et al., 1999).

Some synthetic neurosteroids that show better pharmacokinetics andefficacy are evaluated for sedative and anxiolytic (minaxolone),anesthetic (alphaxolone) and antiepileptic (ganax ol one) effects.

However, the diverse in vivo actions of neuroactive steroids depend onthe lack of specificity of natural and synthetic steroids that do notbind uniquely to one neurotransmitter receptor but on several of them.The metabolism of neuroactive steroids with metabolites that exhibitdifferent pharmacological profiles compared to their precursors is alsoresponsible for the variety of effects of a single steroid. As yet, noderivatives of naturally occurring or synthetic steroids have beendeveloped that show exclusive receptor specificity or avoid side effectsdue to it metabolization.

SUMMARY OF THE INVENTION

Among the naturally occurring steroid, studies that demonstrate an invivo effect by pregnenolone are very few but they suggest a beneficialrole for this steroid. It was shown that pregnenolone administrationdecreased the formation of gliotic tissue following a penetrating lesionin rat cerebral cortex and hippocampus (Garcia-Estrada et al., 1999).Pregnenolone was showed to protect against toxicity induced by glutamateand the protein beta amyloid in hippocampal cells line (HT-22) cultures(Gursoy et al., 2001). Furthermore, pregnenolone has also been suggestedto enhance memory performance (Mathis et al., 1994). However, theseeffects of pregnenolone have been classically attributed to thedownstream metabolites of pregnenolone, that in itself is considered theinactive precursor of downstream active steroids. Thus, pregnenolone hasnot effects on the principal targets of neuroactive steroids that arethe GABA and Excitatory aminoacid receptors.

Recently, the inventors have shown that pregnenolone acts as aninhibitor of the human CB1 receptor with a pharmacological profiledifferent from orthosteric antagonist and from other neuroactivesteroids, which indicates that pregnenolone has less unspecific andundesiderable effects than orthosteric antagonists of the CB1 and otherneuroactive steroids (patent application PCT/EP2012/059310 publishedunder WO2012/160006; Vallée et al., 2013).

Given that pregnenolone is the first step of steroid synthesis in thebrain and other organ, pregnenolone is not considered as a good targetto derive synthetic neuroactive steroids from.

Indeed, such pregnenolone derivatives present high risk to bemetabolised. The generated metabolites could exhibit differentpharmacological profiles compared to their precursors and exert sideeffects.

The inventors have found that molecules derived from pregnenolone thatcontain a 3-benzyloxy function (substituted or not) cannot be convertedinto metabolites endowed with progestative, androgenic, estrogenic, andglucocorticoid activity. Therefore, using these pregnenolone derivativesthat are not or not substantially converted into pregnenolonemetabolites avoids side effects.

Thus, the present invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof,

wherein:

-   -   R1 is:

C1-8 alkyl,

C1-8 alkoxy,

CN,

NO₂,

amino,

COOH,

COOCH₃

OH,

N₃,

or

halogen

and

-   -   R2 is:

H,

OH,

C1-8 alkyl,

C1-8 alkoxy,

C2-C6 alkenyl,

halogen,

Bn-O—

Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO₂, amino,COOH or halogen or

Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO₂, amino,COOH or halogen.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “Agonist” refers to a compound that enhances the activity ofanother compound or receptor site.

The terms “Antagonist” and “Inhibitor” refer to a compound thatdiminishes or prevents the activity of another compound at a receptorsite and more generally refer to a compound that diminishes or preventsthe activation and/or the activity of a receptor.

The terms “Treatment or treating” refer to both therapeutic treatmentand prophylactic or preventive measures, wherein the object is toprevent or slow down the targeted pathologic condition or disorder.Those in need of treatment include those already with the disorder aswell as those prone to have the disorder or those in whom the disorderis to be prevented. Hence, the subject to be treated herein may havebeen diagnosed as having the disorder or may be predisposed orsusceptible to the disorder.

As used herein, the term “subject” denotes a mammal, such as a rodent, afeline, a canine, and a primate. Preferably, a subject according to theinvention is a human.

A “therapeutically effective amount” is intended for a minimal amount ofactive agent which is necessary to impart therapeutic or a preventivebenefit to a subject. For example, a “therapeutically effective amount”to a mammal is such an amount which induces, ameliorates or otherwisecauses an improvement in the pathological-symptoms, disease progressionor physiological conditions associated with or resistance to succumbingto a disorder.

“Alkyl” means monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms. C1-8 alkyl meansa linear or branched alkyl having from one to eight carbon atoms.

“Alkoxy” means a moiety of the formula —OR, wherein R is an alkyl moietyas defined herein.

The term “alkenyl” used herein describes an unsaturated, linear orbranched aliphatic hydrocarbon having at least one carbon-carbon doublebond. “C2-6 alkenyl” denotes a straight- or branched-chain of 2 to 6carbon atoms with at least one double bond.

The term “halogen”, alone or in combination with other groups, denoteschloro (Cl), iodo (I), fluoro (F) and bromo (Br).

The term “cyano”, alone or in combination with other groups, denotes thegroup —CN.

The term “hydroxyl”, alone or in combination with other groups, denotesthe group —OH.

The term “nitro”, alone or in combination with other groups, denotes thegroup —NO₂.

The term “carboxyl”, alone or in combination with other groups, denotesthe group —COOH.

“Amino” means a moiety of the formula —NRR′ wherein R and R′ eachindependently is hydrogen, or alkyl as defined herein.

The abbreviation Bn refers to a benzyl group.

The abbreviation Ph refers to a phenyl group.

The term “pharmaceutically acceptable salts” refers to salts that aresuitable for use in contact with the tissues of humans and animalswithout undue toxicity, irritation, allergic response, and the like.Examples of suitable salts include salts of alkali metals such aspotassium, sodium, lithium, salts of alkaline earth metals such ascalcium, magnesium and acid addition salts with inorganic and organicacids are, but are not limited to, hydrochloric acid, nitric acid,sulphuric acid, phosphoric acid, sulphuric acid, citric acid, formicacid, fumaric acid, maleic acid, lactic acid, malic acid, acetic acid,succinic acid, hemisuccinic acid, tartaric acid, methane-sulfonic acid,p-toluenesulphonic acid, trifluoro acetic acid and the like.

Substituents above the plane of the molecule are shown as a solid line (

)and are described as β; those below the plane are shown by a brokenline (

) and are described as α.

Compounds of the Invention General Formula

The invention relates to compounds of Formula I or pharmaceuticallyacceptable salts thereof:

wherein:

-   -   R1 is:

C1-8 alkyl,

C1-8 alkoxy,

CN,

NO₂,

amino,

COOH,

COOCH₃

OH,

N₃,

or

halogen

and

-   -   R2 is:

H,

OH,

C1-8 alkyl,

C1-8 alkoxy,

C2-C6 alkenyl,

halogen,

Bn-O—

Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO₂, amino,COOH or halogen

or

Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO₂, amino,COOH or halogen.

In one preferred embodiment, R2 is in α position.

In this embodiment, the compounds of the invention have the Formula II:

wherein:

-   -   R1 is:

C1-8 alkyl,

C1-8 alkoxy,

CN,

NO₂,

amino,

COOH,

COOCH₃,

OH,

N₃,

or

halogen

and

-   -   R2 is:

H,

OH,

C1-8 alkyl,

C1-8 alkoxy,

C2-C6 alkenyl,

halogen,

Bn-O—

Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO₂, amino,COOH or halogen

or

Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO₂, amino,COOH or halogen.

In a preferred embodiment, R1 is OH, C1-8 alkyl, C1-8 alkoxy or halogen,more preferably R1 is OH, methyl, ethyl, methoxy, ethoxy, methylcarboxy,Cl, Br, F or cyano.In a preferred embodiment, R2 is H, OH, C1-8 alkyl, C1-8 alkoxy, C1-8alkenyl or Bn, more preferably R2 is H, OH, methyl, ethyl, methoxy,ethoxy, allyl or Bn.More preferably, the compound of the invention is:3-(p-hydroxybenzyloxy)-pregnenolone,3-(p-methylbenzyloxy)-pregnenolone,3-(p-ethylbenzyloxy)-pregnenolone,3-(p-methoxybenzyloxy)-pregnenolone,3-(p-ethoxybenzyloxy)-pregnenolone,3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-pregnenolone,3-(p-chlorobenzyloxy)-pregnenolone,3-(p-bromobenzyloxy)-pregnenolone,3-(p-cyanobenzyloxy)-pregnenolone,17-hydroxy-3-(p-hydroxybenzyloxy)-pregnenolone,17-hydroxy-3-(p-methylbenzyloxy)-pregnenolone,3-(p-ethylbenzyloxy)-17-hydroxy-pregnenolone,17-hydroxy-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-ethoxybenzyloxy)-17-hydroxy-pregnenolone,17-hydroxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-17-hydroxy-pregnenolone,3-(p-chlorobenzyloxy)-17-hydroxy-pregnenolone,3-(p-bromobenzyloxy)-17-hydroxy-pregnenolone,3-(p-cyanobenzyloxy)-17-hydroxy-pregnenolone,3-(p-hydroxybenzyloxy)-17-methyl-pregnenolone,17-methyl-3-(p-methylbenzyloxy)-pregnenol one,3-(p-ethylbenzyloxy)-17-methyl-pregnenolone,3-(p-methoxybenzyloxy)-17-methyl-pregnenolone,3-(p-ethoxybenzyloxy)-17-methyl-pregnenolone,17-methyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-17-methyl-pregnenolone,3-(p-chlorobenzyloxy)-17-methyl-pregnenolone,3-(p-bromobenzyloxy)-17-methyl-pregnenolone,3-(p-cyanobenzyloxy)-17-methyl-pregnenolone,17-ethyl-3-(p-hydroxybenzyloxy)-pregnenolone,17-ethyl-3-(p-methylbenzyloxy)-pregnenolone,17-ethyl-3-(p-ethylbenzyloxy)-pregnenolone,17-ethyl-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-ethoxybenzyloxy)-17-ethyl-pregnenolone,17-ethyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-ethyl-3-(p-fluorobenzyloxy)-pregnenolone,3-(p-chlorobenzyloxy)-17-ethyl-pregnenolone,3-(p-bromobenzyloxy)-17-ethyl-pregnenolone,3-(p-cyanobenzyloxy)-17-ethyl-pregnenolone,3-(p-hydroxybenzyloxy)-17-methoxy-pregnenolone,17-methoxy-3-(p-methylbenzyloxy)-pregnenolone,3-(p-ethylbenzyloxy)-17-methoxy-pregnenolone,17-methoxy-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-ethoxybenzyloxy)-17-methoxy-pregnenolone,17-methoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-17-methoxy-pregnenolone,3-(p-chlorobenzyloxy)-17-methoxy-pregnenolone,3-(p-bromobenzyloxy)-17-methoxy-pregnenolone,3-(p-cyanobenzyl oxy)-17-methoxy-pregnenolone,17-ethoxy-3-(p-hydroxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-methylbenzyloxy)-pregnenolone,17-ethoxy-3-(p-ethylbenzyloxy)-pregnenolone,17-ethoxy-3-(p-methoxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-ethoxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-fluorobenzyloxy)-pregnenolone,3-(p-chlorobenzyloxy)-17-ethoxy-pregnenolone,3-(p-bromobenzyloxy)-17-ethoxy-pregnenolone,3-(p-cyanobenzyloxy)-17-ethoxy-pregnenolone,17-allyl-3-(p-hydroxybenzyloxy) -pregnenolone,17-allyl-3-(p-methylbenzyloxy)-pregnenolone,17-allyl-3-(p-ethylbenzyloxy)-pregnenolone,17-allyl-3-(p-methoxybenzyloxy)-pregnenolone,17-allyl-3-(p-ethoxybenzyloxy)-pregnenolone,17-allyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-allyl-3-(p-fluorobenzyloxy)-pregnenolone,17-allyl-3-(p-chlorobenzyloxy)-pregnenolone,17-allyl-3-(p-bromobenzyloxy)-pregnenolone,17-allyl-3-(p-cyanobenzyloxy)-pregnenol one,17-benzyl-3-(p-hydroxybenzyloxy)-pregnenolone,17-benzyl-3-(p-methylbenzyloxy)-pregnenolone,17-benzyl-3-(p-ethylbenzyloxy)-pregnenolone,17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone,17-benzyl-3-(p-ethoxybenzyloxy)-pregnenolone,17-benzyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-benzyl-3-(p-fluorobenzyloxy)-pregnenolone17-benzyl-3-(p-chlorobenzyloxy)-pregnenolone17-benzyl-3-(p-bromobenzyloxy)-pregnenolone or17-benzyl-3-(p-cyanobenzyloxy)-pregnenolone.

The preferred compounds of the invention is selected from the groupconsisting of 3β-(p-Methoxybenzyloxy)-17α-methyl-pregnenolone,17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-methoxybenzyloxy)-pregnenolone, 3-(p -bromobenzyloxy)-pregnenolone,3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-methylbenzyloxy)-pregnenolone, 3-(p-fluorobenzyloxy)-pregnenoloneand 3-(p-cyanobenzyloxy)-pregnenolone.

The preferred compound of the invention is3β-(p-Methoxybenzyloxy)-17α-methyl-pregnenolone.

The invention also relates to a pharmaceutical composition comprising acompound of the invention or a pharmaceutically salt thereof and apharmaceutically acceptable carrier.

Process for the Manufacture

The present invention also relates to a process for the manufacture ofthe compounds of the invention, which comprises reacting a compound ofFormula III:

wherein R2 is as defined above,

with a compound of Formula IV:

wherein R1 is as defined above,

in the presence of a heterogeneous acid scavenger and of methyl triflate

or

with a compound of Formula V

wherein R1 is as defined above

in the presence of a heterogeneous acid scavenger.

In case of a compound of formula V, there is no need for the presence ofmethyl triflate due to the OTf group.

In one embodiment, the process for the manufacture of the compounds ofthe invention, comprises reacting a compound of Formula III:

wherein R2 is as defined above,

with a compound of Formula IV:

wherein R1 is as defined above,

in the presence of a heterogeneous acid scavenger and of methyltriflate.

In another embodiment, the process for the manufacture of the compoundsof the invention, comprises reacting a compound of Formula III:

wherein R2 is as defined above,

with a compound of Formula V

wherein R1 is as defined above

in the presence of a heterogeneous acid scavenger.

Preferably, the solvent for this reaction is an aromatic solvent such astrifluorotoluene or toluene.

Preferably, the heterogeneous acid scavenger is potassium carbonate ormagnesium oxide.

Method for synthesis of compounds of formula III are well described inthe prior art (Glazier E. R., 1962, Marshall et al., 1948, Jones et al.,1965).

For example, synthesis of a compound of formula III wherein R2 is analkyl, -allyl, -benzyl or -aryl may be done by reacting pregnenolonewith Ac₂O to form a enol acetate. Then, the enol acetate is reacted witha Grignard reagent to generate an enolate which is subsequently trappedwith a halogeno-R2.

Further, for example, synthesis of a compound of formula III wherein R2is an alkoxy, benzyloxy or aryloxy may be is done by reactingpregnenolone with the corresponding alcohol in the presence of Cu²⁺.

Method of Treatment

The present invention also relates to a compound of the invention asdefined above or a pharmaceutically acceptable salt thereof for use in amethod for treatment of the human or animal body.

The present invention also relates to a method for the treatment of apathologic condition or disorder in a subject in need thereof comprisingadministering to said subject an effective amount of a compound of theinvention as defined above or a pharmaceutically acceptable saltthereof.

The pathologies that may be treated with the compounds of the inventionare those which may be treated by Pregnenolone, for example thepathologies that may be treated by Pregnenolone because of it action asan inhibitor of the CB1 receptor.

Examples of such pathologies are psychiatric and neurological disorders;neurodegenerative disorders; metabolic disorders; addiction, dependence,abuse relapse and related disorders; bladder and gastrointestinaldisorders; hepatic diseases such as steatosis; non-alcoholicsteatohepatitis (NASH), liver cirrhosis; alcoholic steatosis;inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma;spasticity; cancer; osteoporosis; obesity; autoimmune hepatitis andencephalitis; pain or reproductive disorders and skin inflammatory andfibrotic diseases.

The present invention also relates to the use of compounds of theinvention or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for treating one of the above mentionedpathologies.

The invention will be further illustrated by the following figures andexamples. However, these examples and figures should not be interpretedin any way as limiting the scope of the present invention.

EXAMPLES A. Examples of Synthesis of Pregnenolone Derivatives

Pregnenolone is a well-known and commercially available steroid (CASnumber 145-13-1).

As shown below, Pregnenolone can be used as precursor for the synthesisof its derivatives.

1. Synthesis of Pregnenolone Derivatives Substituted in C17

First, Pregnenolone is substituted in C17.

Example of Synthesis of a Pregnenolone Derivative Having C17 SubstitutedWith R

As shown below, to synthesize a Pregnenolone substituted with an alkyl,an allyl or an aryl at C17 position, in a first step, the correspondingenol acetate is formed by reacting Pregnenolone with Ac₂O. Then, theenol acetate is reacted with a Grignard reagent such as MeMgBr in THF togenerate an enolate which is subsequently trapped with an electrophile.The electrophile would be preferentially an R-iodo- or R-bromo wherein Ris an alkyl, -allyl, -benzyl or -aryl.

Example of Synthesis of the Enol Acetate Intermediate

As shown below, p-toluenesulfonic acid monohydrate (1.12 g; 5.9 mmol;0.93 eq.) was added to a solution of Pregnenolone (2 g; 6.3 mmol; 1 eq.)in acetic anhydride (230 ml). The reaction medium was stirred for 5 h atreflux and acetic anhydride was slowly distilled. After allowed to coolto 20° C., the reaction medium was poured into crushed ice then themixture is extracted with diethyl ether. The organic layer was washedwith saturated aqueous Na₂CO₃, dried over Na₂SO₄ then evaporated underreduced pressure. The residue was purified by chromatography on silicagel (eluent: cyclohexane/AcOEt from 100/0 to 90/10) to give thePregnenolone enol acetate (2.2 g; 85%) as a white solid.

Example of Synthesis of the 17α-methyl-pregnenolone

As shown below, MeMgBr₂ (3M in Et₂O; 25 ml; 75 mmol; 10 eq.) was addedto a solution of pregnenolone enol acetate (3 g; 7.5 mmol; 1 eq.) inanhydrous THF (65 ml). The reaction medium was stirred for 1 h atreflux, then allowed to cool to 20° C. CH₃I (4.6 ml; 75 mmol; 10 eq.)was added and reaction medium was stirred at reflux. Adding CH₃I wasrepeated every 45 minutes until 40 equivalents. After cooling to 20° C.,an aqueous solution of NH₄Cl is added then the mixture is extracted withethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ then evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel (eluent: cyclohexane/AcOEt 75/25) togive the 17α-methyl-pregnenolone (600 mg; 25%) as a white solid.

Example of Synthesis of a Pregnenolone Derivative Having C17 SubstitutedWith —OR

To synthesize a Pregnenolone substituted with an alkoxy-, benzyloxy- oraryloxy- at C17 position, Pregnenolone is reacted with the correspondingalcohol, —R—OH, in the presence of Cu²⁺.

Example of Synthesis of 17-methoxy-pregnenolone

As shown below, CuBr₂ (4.05 g; 18.13 mmol; 1.9 eq.) was added to asuspension of pregnenolone (3 g; 9.48 mmol; 1 eq.) in methanol (360 ml).The reaction medium was stirred for 24 h at reflux, then evaporatedunder reduced pressure. The residue was dissolved in dichloromethane andwater. The organic layer was washed with brine, dried over Na₂SO₄ thenconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (eluent:cyclohexane/AcOEt 80/20) then byrecrystallisation (acetone) to give the 17-methoxy-pregnenolone (510 mg;15%) as a white solid.

2. Synthesis of Compound of Formula IV

Some compounds of formula IV may be commercially available for example2-(4-methoxybenzyloxy)-4-methylquinoleine.

Compounds of formula IV may also be synthetized by reacting2-chloro-4-methylquinoleine and para-substituted benzyl alcohol in thepresence of 18-crown-6 and KOH according the schema below.

Example of Synthesis of 2-(p-methylbenzyloxy)-4-methylquinoline

As shown below, to a solution of 2-chloro-4-methylquinoleine-(500 mg;2.8 mmol; 1 eq.) in anhydrous toluene (10 mL) was added successively4-methylbenzyl alcohol (409 mg, 3.35 mmol; 1.25 eq), KOH (630 mg; 11.2mmol; 4.0 eq.), then 18-crown-6 (45 mg, 0.16 mmol, 0.06 eq). Thereaction medium was heated at reflux for 1.5 h using a Dean-Stark trap.The reaction medium was then cooled to room temperature then water wasadded and product is extracted with AcOEt. The organic phase is dried(Na₂SO₄) then evaporated under vacuum. The residue was purified bychromatography on silica gel (eluent: cyclohexane/AcOEt 95/5) to give2-(p-methylbenzyloxy)-4-methylquinoline (660 mg; 89%) as a colorlessoil.

3. Synthesis of Compounds of Formula V

Compounds of formula V may be synthetized in two steps: First byreacting 2-chloropyridine and para-substituted benzyl alcohol in thepresence of 18-crown-6 and KOH or t-BuOK; Second by reacting theresulting product with methyl triflate to allow the salt formationaccording to the schema below.

Example of Synthesis of 2-(p-Bromobenzyloxy)-1-methylpyridinium Triflate

As shown below, to a solution of 2-chloropyridine (0.9 mL; 9.6 mmol; 1.2eq.) in anhydrous toluene (16 mL) was added successively 4-Bromobenzylalcohol (1.5 g, 8.0 mmol; 1 eq), KOH (1.35 g; 24 mmol; 3.0 eq.), then18-crown-6 (105 mg, 0.4 mmol, 0.05 eq). The reaction medium was stirredat reflux for 1 h using a Dean-Stark trap. The reaction medium wascooled to room temperature then water was added and product wasextracted with AcOEt. The organic phase is dried (Na₂SO₄) thenevaporated under vacuum. The residue was purified by chromatography onsilica gel (eluent:cyclohexane/AcOEt 9/1) to give2-(p-Bromobenzyloxy)-pyridine (2 g; 78%) as a colorless oil.

For the second step, methyl triflate, MeOTf, (450 μL; 3.97 mmol; 1.05eq) was added to a cold solution of 2-(p-bromobenzyloxy)-pyridine (1 g;3.7 mmol; 1 eq). The reaction medium was stirred for 2 hours at roomtemperature then evaporated under vacuum to give quantitatively2-(p-Bromobenzyloxy)-1-methylpyridinium Triflate (1.6 g) as a whitesolid.

Example of Synthesis of 2-(p-Methylcarboxybenzyloxy)-1-methylpyridiniumTriflate

As shown below, to a solution of 2-chloropyridine (1.13 mL; 12.0 mmol;1.0 eq.) in anhydrous dioxane (48 mL) was added successively4-Methylcarboxy-benzyl alcohol (1.5 g, 8.0 mmol; 1 eq) and t-BuOK (2 g;18 mmol; 1.5 eq.). The reaction medium was heated at reflux for 16 h.The reaction medium was cooled to room temperature then water was addedand product is extracted with AcOEt. The organic phase is dried (Na₂SO₄)then evaporated under vacuum. The residue was purified by chromatographyon silica gel (eluent: cyclohexane/AcOEt 96/4) to give2-(p-Methylcarboxybenzyloxy)-pyridine (1.13g; 39%) as a colorless oil.For the second step, MeOTf, (293 μL; 2.59 mmol; 1.05 eq) was added to acold solution of 2-(p-Methylcarboxybenzyloxy)-pyridine (600 mg; 2.46mmol; 1 eq). The reaction medium was stirred for 2 hours at roomtemperature then evaporated under vacuum to give quantitatively2-(p-Methylcarboxybenzyloxy)-1-methylpyridinium Triflate (0.9 g) as awhite solid.

4. Synthesis of Pregnenolone Derivatives Having C3 Substituted WithPara-substituted Benzyloxy

Starting from Pregnenolone or Pregnenolone derivative having thesuitable group in C17, the pregnenolone or pregnenolone derivative issubstituted in C3 with a group OBn-R1 according to known methods ofbenzylation of alcohol (Poon KWC. et al. 2006, Giannis et al., 2009,Nwoye, E. O et al., 2007) and as shown below.

Example of Benzylation of Pregnenolone

As shown below, MgO (46 mg; 1.14 mmol; 2 eq.) and2-benzyloxy-1-methylpyridinium triflate (400 mg; 1.14 mmol; 2.0 eq.)were added to a solution of pregnenolone (181 mg; 0.57 mmol; 1 eq.) intrifluorotoluene (4 ml). The reaction medium was stirred for one nightat 85° C., then filtered on celite and evaporated under reducedpressure. The residue was purified by chromatography on silica gel(eluent:cyclohexane/AcOEt 95/5) to give the 3β-benzyloxy-pregnenolone(0.16 g; 70%) as a white solid.

Example of Benzylation of 17α-benzylpregnenolone

As shown below, MgO (116 mg; 2.42 mmol; 2.0 eq.) and2-benzyloxymethylpyridinium triflate (1 g; 2.86 mmol; 2.0 eq.) wereadded to a solution of 17α-benzylpregnenolone (580 mg; 1.43 mmol; 1 eq.)in trifluorotoluene (15 ml). The reaction medium was stirred for onenight at 85° C., then filtered on celite and evaporated under reducedpressure. The residue was purified by chromatography on silica gel(eluent:cyclohexane/AcOEt 95/5) to give the3β-benzyloxy-17α-benzyl-pregnenolone (300 mg; 42%) as a white solid.

Example of Synthesis of the 3β-(p-bromobenzyloxy)-pregnenolone

A shown below, to a solution of pregnenolone (477 mg; 1.51 mmol; 1 eq.)in anhydrous α,α,α-trifluorotoluene (9 mL) was added MgO (121 mg; 3.02mmol; 2.0 eq.) then 2-(p-Bromobenzyloxy)-1-methylpyridinium Triflate(1.29 g; 3.02 mmol; 2.0 eq.). The reaction medium was stirred for 20 hat 100° C., and then filtered on celite. Water was added and product isextracted with AcOEt. The organic phase is dried (Na₂SO₄) thenevaporated under vacuum. The residue was purified by chromatography onsilica gel (eluent: cyclohexane/AcOEt 96/4) then triturated with acetoneto give the 3β-(p-bromobenzyloxy)-pregnenolone (375mg; 49%) as a whitesolid.

Example of Synthesis of 3β-(p-Methoxybenzyloxy)-pregnenolone

As shown below, to a solution of pregnenolone (250 mg; 0.79 mmol; 1 eq.)in anhydrous toluene was added successively MgO (63 mg; 1.58 mmol; 2.0eq.), 2-(4-methoxybenzyloxy)-4-methylquinoleine (441 mg; 1.58 mmol; 2.0eq.) and methyl triflate (MeOTf) (180 μl; 1.58 mmol; 2 eq). The reactionmedium was stirred for 20 h at 60° C., and then filtered on celite.Water was added and product is extracted with AcOEt. The organic phaseis dried (Na₂SO₄) then evaporated under vacuum. The residue was purifiedby chromatography on silica gel (eluent: cyclohexane/AcOEt 9/1) to givethe 3β-(p-methoxybenzyloxy)-pregnenolone (160 mg; 43%) as a white solid.

Example of Synthesis of 3β-(p-methoxybenzyloxy)-17α-methyl-pregnenolone

17α-methyl-pregnenolone was synthesized as shown above.

To a solution of 17α-methyl-pregnenolone (170 mg; 0.5 mmol; 1 eq.) inanhydrous toluene was added successively MgO (40 mg; 1 mmol; 2 eq.),2-(4-methoxybenzyloxy)-4-methylquinoleine (290 mg; 1 mmol; 2 eq), andmethyl triflate (MeOTf) (0.11 ml; 1 mmol; 2 eq). The reaction medium wasstirred for one night at 85° C., and then filtered on celite. Water wasadded and product is extracted with AcOEt. The organic phase is dried(Na₂SO₄) then evaporated under vacuum. The residue was purified bychromatography on silica gel (eluent: cyclohexane/AcOEt from 1/0 to95/5) then triturated with acetone to give the3β-(p-Methoxybenzyloxy)-17α-methyl-pregnenolone (80 mg; 35%) as a whitesolid.

Example of Synthesis of 3β-(p-methoxybenzyloxy)-17α-benzyl-pregnenolone

17α-benzyl-pregnenolone was synthesized as shown above.

To a solution of 17α-benzyl-pregnenolone (1.9 g; 4.66 mmol; 1 eq.) inanhydrous toluene (45 ml) was added successively MgO (373 mg; 9.3 mmol;2 eq.), 2-(4-methoxybenzyloxy)-4-methylquinoleine (2.6 g; 9.33 mmol; 2eq), and methyl triflate (MeOTf) (1.06 ml; 9.33 mmol; 2 eq). Thereaction medium was stirred for one night at 40° C., and then filteredon celite. Water was added and product is extracted with AcOEt. Theorganic phase is dried (Na₂SO₄) then evaporated under vacuum. Theresidue was purified by chromatography on silica gel (eluent:cyclohexane/AcOEt 9/1) then triturated with acetone to give the3β-(p-methoxybenzyloxy)-17α-benzyl-pregnenolone (1.18 g; 49%) as a whitesolid.

B. Capacity of Pregnenolone Derivatives Not To Be Converted In OtherActive Steroids Derived From Pregnenolone Material and Methods

In Vitro Test of Metabolization

Alternatively the compound can be administered to any cell lineexpressing the enzyme that metabolizes pregnenolone in culture,measuring then the content of metabolites of pregnenolone within thecell or on the cell culture medium by GC/MS and comparing theseconcentrations to metabolites in cell cultures that have been receivedonly a vehicle or pregnenolone.

In this example, CHO cell line was used. These cells derived from theovary have all the enzymes needed to metabolize pregnenolone indownstream steroids.

The content in CHO culture medium of allopregnanolone (ALLO),epiallopregnanolone (EPIALLO), pregnenolone (PREG), DHEA, andtestosterone (TESTO) was measured by GC/MS.

Results

Pregnenolone Derivatives for Which the Transformation in DownstreamActive Steroids in Vitro is Limited.

The inventors have analyzed the metabolism of pregnenolone derivativesusing an in vitro test in CHO cells.

The administration of Pregnenolone (1 μM) to these cells for 48 hoursproduced a significant increase in Allopregnanolone andEpiallopregnanolone in the culture medium (Table 1).

TABLE 1 Table 1: Pregnenolone metabolism ALLO EPIALLO PREG DHEA TESTOControl cell cultures Steroid 0.00 0.00 96.92 0.00 0.00 Pregnenolone (1μM) levels 3529.99 16963.84 11440.66 0.00 0.00 treated cells pg/ml

Pregnenolone derivatives having C3 substituted with benzyloxy weretested using in vitro test in CHO cells.

Results are shown in Table 2 below. Results expressed as percentagechanges from CHO cells treated with Pregnenolone or as pg/ml(0=concentrations below the detection limit).

TABLE 2 % changes from Reduced metabolim Pregnenolone treated cellspg/ml N° Name Structure ALLO EPIALLO PREG DHEA TESTO 42 3β-Benzyloxy-17α-methyl- pregnenolone

−99.87 −99.94 −100.00 0.00 0.00 63 17α-Benzyl-3β- benzyloxy-pregnenolone

−99.01 −99.84 −99.87 0.00 0.00 41 3β-Benzyloxy- pregnenolone

−98.82 −99.88 −99.35 0.00 0.00 68 3β-(p-methoxy- benzyloxy)-17α- methyl-pregnenolone

−100.00 −100.00 −100.00 0.00 0.00

As shown in table 2, the compound 68,3β-(p-Methoxybenzyloxy)-17α-methyl-pregnenolone, is not metabolised inPregnenolone and the compounds 63 and 41 are not significantlymetabolized in Pregnenolone (metabolization<1%).

Pregnenolone derivatives that contain a 3-benzyloxy function(substituted or not) show no detectable metabolization of derivative ofPregnenolone in DHEA and Testosterone and very low metabolization inAllopregnanolone and Epiallopregnanolone.

These results show the presence of a OBn-R group in C3 avoid theconversion of Pregnenolone derivatives into Pregnenolone andPregnenolone metabolites, in particular metabolites whose Pregnenoloneis precursor and that are endowed with progestative, androgenic,estrogenic, glucocorticoid activity, or neuromodulatory properties.

REFERENCES

Throughout this application, various references describe the state ofthe art to which this invention pertains. The disclosures of thesereferences are hereby incorporated by reference into the presentdisclosure.

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1. A compound of Formula I or a pharmaceutically acceptable saltthereof,

wherein: R1 is selected from the group consisting of C1-8 alkyl, C1-8alkoxy, CN, NO₂, amino, COOH, COOCH₃, OH, N₃, and halogen; and R2 isselected from the group consisting of H, OH, C1-8 alkyl, C1-8 alkoxy,C2-C6 alkenyl, halogen, Bn-O-Bn- and and Ph-.
 2. The compound accordingto claim 1 wherein R2 is in α position.
 3. The compound according toclaim 1 wherein R1 is selected from the group consisting of OH, C1-8alkyl, C1-8 alkoxy, and halogen.
 4. The compound according to claim 1wherein R1 is selected from the group consisting of OH, methyl, ethyl,methoxy, ethoxy, methylcarboxy, Cl, Br, F, and cyano.
 5. The compoundaccording to claim 1 wherein R2 is selected from the group consisting ofH, OH, C1-8 alkyl, C1-8 alkoxy, C1-8 alkenyl, and Bn.
 6. The compoundaccording to claim 1 wherein R2 is selected from the group consisting ofH, OH, methyl, ethyl, methoxy, ethoxy, allyl, and Bn.
 7. The compoundaccording to claim 1 wherein said compound is selected from the groupconsisting of: 3-(p-hydroxybenzyloxy)-pregnenolone,3-(p-methylbenzyloxy)-pregnenolone, 3-(p-ethylbenzyloxy)-pregnenolone,3-(p-methoxybenzyloxy)-pregnenolone, 3-(p-ethoxybenzyloxy)-pregnenolone,3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-pregnenolone, 3-(p-chlorobenzyloxy)-pregnenolone,3-(p-bromobenzyloxy)-pregnenolone, 3-(p-cyanobenzyloxy)-pregnenolone,17-hydroxy-3-(p-hydroxybenzyloxy)-pregnenolone,17-hydroxy-3-(p-methylbenzyloxy)-pregnenolone,3-(p-ethylbenzyloxy)-17-hydroxy-pregnenolone,17-hydroxy-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-ethoxybenzyloxy)-17-hydroxy-pregnenolone,17-hydroxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-17-hydroxy-pregnenolone,3-(p-chlorobenzyloxy)-17-hydroxy-pregnenolone,3-(p-bromobenzyloxy)-17-hydroxy-pregnenolone,3-(p-cyanobenzyloxy)-17-hydroxy-pregnenolone,3-(p-hydroxybenzyloxy)-17-methyl-pregnenolone,17-methyl-3-(p-methylbenzyloxy)-pregnenolone,3-(p-ethylbenzyloxy)-17-methyl-pregnenolone,3-(p-methoxybenzyloxy)-17-methyl-pregnenolone,3-(p-ethoxybenzyloxy)-17-methyl-pregnenolone,17-methyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-17-methyl-pregnenolone,3-(p-chlorobenzyloxy)-17-methyl-pregnenolone,3-(p-bromobenzyloxy)-17-methyl-pregnenolone,3-(p-cyanobenzyloxy)-17-methyl-pregnenolone,17-ethyl-3-(p-hydroxybenzyloxy)-pregnenolone,17-ethyl-3-(p-methylbenzyloxy)-pregnenolone,17-ethyl-3-(p-ethylbenzyloxy)-pregnenolone,17-ethyl-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-ethoxybenzyloxy)-17-ethyl-pregnenolone,17-ethyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-ethyl-3-(p-fluorobenzyloxy)-pregnenolone,3-(p-chlorobenzyloxy)-17-ethyl-pregnenolone,3-(p-bromobenzyloxy)-17-ethyl-pregnenolone,3-(p-cyanobenzyloxy)-17-ethyl-pregnenolone,3-(p-hydroxybenzyloxy)-17-methoxy-pregnenolone,17-methoxy-3-(p-methylbenzyloxy)-pregnenolone,3-(p-ethylbenzyloxy)-17-methoxy-pregnenolone,17-methoxy-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-ethoxybenzyloxy)-17-methoxy-pregnenolone,17-methoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-fluorobenzyloxy)-17-methoxy-pregnenolone,3-(p-chlorobenzyloxy)-17-methoxy-pregnenolone,3-(p-bromobenzyloxy)-17-methoxy-pregnenolone,3-(p-cyanobenzyloxy)-17-methoxy-pregnenolone,17-ethoxy-3-(p-hydroxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-methylbenzyloxy)-pregnenolone,17-ethoxy-3-(p-ethylbenzyloxy)-pregnenolone,17-ethoxy-3-(p-methoxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-ethoxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-ethoxy-3-(p-fluorobenzyloxy)-pregnenolone,3-(p-chlorobenzyloxy)-17-ethoxy-pregnenolone,3-(p-bromobenzyloxy)-17-ethoxy-pregnenolone,3-(p-cyanobenzyloxy)-17-ethoxy-pregnenolone,17-allyl-3-(p-hydroxybenzyloxy)-pregnenolone,17-allyl-3-(p-methylbenzyloxy)-pregnenolone,17-allyl-3-(p-ethylbenzyloxy)-pregnenolone,17-allyl-3-(p-methoxybenzyloxy)-pregnenolone,17-allyl-3-(p-ethoxybenzyloxy)-pregnenolone,17-allyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-allyl-3-(p-fluorobenzyloxy)-pregnenolone,17-allyl-3-(p-chlorobenzyloxy)-pregnenolone,17-allyl-3-(p-bromobenzyloxy)-pregnenolone,17-allyl-3-(p-cyanobenzyloxy)-pregnenolone,17-benzyl-3-(p-hydroxybenzyloxy)-pregnenolone,17-benzyl-3-(p-methylbenzyloxy)-pregnenolone,17-benzyl-3-(p-ethylbenzyloxy)-pregnenolone, 17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone,17-benzyl-3-(p-ethoxybenzyloxy)-pregnenolone,17-benzyl-3-(p-methylcarboxybenzyloxy)-pregnenolone,17-benzyl-3-(p-fluorobenzyloxy)-pregnenolone17-benzyl-3-(p-chlorobenzyloxy)-pregnenolone.17-benzyl-3-(p-bromobenzyloxy)-pregnenolone and17-benzyl-3-(p-cyanobenzyloxy)-pregnenolone.
 8. The compound accordingto claim 1 which is selected from the group consisting of3β-(p-Methoxybenzyloxy)-17α-methyl-pregnenolone,17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone,3-(p-methoxybenzyloxy)-pregnenolone, 3-(p-bromobenzyloxy)-pregnenolone,3-(p-methylcarboxybenzyloxy)-pregnenolone,3-(p-methylbenzyloxy)-pregnenolone, 3-(p-fluorobenzyloxy)-pregnenoloneand 3-(p-cyanobenzyloxy)-pregnenolone.
 9. A pharmaceutical compositioncomprising a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 10. Aprocess for the manufacture of the compound of Formula I according toclaim 1, which comprises reacting a compound of Formula III:

wherein R2 is as defined above, with a compound of Formula IV:

wherein R1 is as defined above, in the presence of methyl triflate andof a heterogeneous acid scavenger or with a compound of Formula V

wherein R1 is as defined above, in the presence a heterogeneous acidscavenger.
 11. A method for treating the human or animal body sufferingfrom a pathology comprising a step of administering the compound asdefined in claim 1 or a pharmaceutically acceptable salt thereof to ahuman or animal in need thereof.
 12. The method for treating the humanor animal body according to claim 11, wherein said pathology is selectedfrom the group consisting of psychiatric and neurological disorders;neurodegenerative disorders; metabolic disorders; addiction, dependence,abuse relapse and related disorders; bladder and gastrointestinaldisorders; hepatic diseases such as steatosis; non-alcoholicsteatohepatitis (NASH), liver cirrhosis; alcoholic steatosis;inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma;spasticity; cancer; osteoporosis; obesity; autoimmune hepatitis andencephalitis; pain or reproductive disorders and skin inflammatory andfibrotic diseases.